Glücksklee, the Quad, and High-Risk Myeloma
Authors: Ajay K. Nooka, Jonathan L. Kaufman, Sagar Lonial
Journal: Journal of Clinical Oncology (2023)

In the article that accompanies this editorial, Leypoldt et al 1 describe the results of a forwardthinking study focused on the management of high-risk newly diagnosed multiple myeloma (HR NDMM) using the quadruplet (quad) regimen: isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd).This multicenter, phase II trial enrolled patients with HR NDMM, cytogenetically defined as the presence of del17p, t(4;14), t(14;16), or more than three copies of 1q21.Patients were not eligible if they had Revised International Staging System (R-ISS) stage I disease.Both transplant-eligible (TE) and transplant-ineligible (TIE) patients received continuous therapy with Isa-KRd induction followed by Isa-KR maintenance interrupted by an autologous stem cell transplant (ASCT) among TE patients or two further cycles of Isa-KRd among TIE patients.Leypoldt et al 1 report the results of the primary end point, which is minimal residual disease (MRD) negativity (<10 -5 MRD by next-generation flow [NGF]) at the end of consolidation.The secondary end point was progression-free survival (PFS).While this was a concept study, how does this set us up for the future in managing patients with HR NDMM?German lore tells us of the good fortune of the Gl ücksklee, the four-leaf clover.Is this trial using a quad regimen for HR NDMM the answer we have been seeking?Let us consider four (lucky) points.First, how do we measure and compare outcomes for a heterogeneous group of patients?The study population included patients with R-ISS II/III disease and presence of fluorescent in situ hybridization/cytogenetics abnormalities of del17p, t(4;14), t(14;16), or 1q21 (>3 copies).The assumption is that all are equally bad, but we now know that is not the case.In the era of immunomodulatory agent (IMiD)/proteasome inhibitor (PI) induction, isolated 1q amp does not carry the same risk as del17p or the combination of amp 1q and del17p.Several trials have confirmed that ≥two high-risk cytogenetic abnormalities (HRCAs) do extremely poorly even with triplet maintenance (IMiD/PI/steroids).Are there data demonstrating that CD38 monoclonal antibody (mAB) improves outcomes in HR NDMM?In the MASTER study, it did not appear to, but that may have been confounded by early discontinuation among patients achieving sustained MRD negativity (threshold of 10 25 as well, but by next-generation sequencing [NGS]) early. 2 A study from our group using carfilzomib, pomalidomide, and dexamethasone as combination maintenance therapy post-ASCT resulted in higher rates of MRD negativity by NGS (10 26 , not 10 25 ), but even here, patients with ≥two HRCAs did worse compared with those who carried only one HRCA. 3In summary, can we call this study a win when isolated 1q21 (>three copies) accounted for a third of the patient population (20% of TE and 45% of TIE) and two thirds of patients had one HRCA (60 of 99 TE patients and 17 of 26 TIE patients), which is considerably higher than what is presented in most studies.In the GRIFFIN trial, 15% had HRCAs (del17p, t[4;14], or t[14;16], or a combination of the above), but this number was upgraded to 41% with the inclusion of 1q21 (≥3 copies). 4The heterogeneity of the population may call for redefining our risk groups rather than broadening the definition of high risk, raising a question of patient selection affecting the reported outcomes.Second, what is the optimal end point for measuring success in high-risk disease?The primary end point in this trial is MRD negativity (<10 25 MRD by NGF cytometry) at the end of consolidation.The secondary end point was PFS.This raises the question of the optimal measure of success (the ideal end point).Achieving MRD negativity is prognostic for PFS and overall survival (OS) in large studies and meta-analyses, but the consistency of when this is measured is variable and often represents the best response. 5,6In high-risk disease, declaring victory early on the basis of the depth of response alone is a dangerous game. 2 This may apply to studies involving patients with long-term remissions, where surrogate end points make sense.Unfortunately, it is not the case here where high-risk patients develop early progression, with early defined as progression much sooner than standard-risk patients.The utility of a surrogate